Novel process for preparing rac-bicalutamide and its intermediates

ABSTRACT

The present invention relates to a new process for the synthesis of racemic and optically active bicalutamide starting from ethyl pyruvate and methyl methacrylate. The present invention discloses processes of preparing bicalutamide intermediates including ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate, 1,2-epoxy-2-methyl propionate and 2-hydrox-2-methyl-3-(4-fluorophenylthio) propionic acid. The present invention further discloses micronized rac-bicalutamide and the preparation thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefits under 35 U.S.C. § 119(e) ofProvisional Application Serial No. 60/298,009, filed Jun. 13, 2001 and60/371,069, filed on Apr. 9, 2002, the disclosures of which areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

[0002] The present invention relates to process for preparingrac-bicalutamide and its intermediates. The prevent invention alsorelates to micronized rac-bicalutamides and their preparations thereof.

BACKGROUND OF THE INVENTION

[0003] Bicalutamide is also known asN-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamideand has the following chemical formula.

[0004] Bicalutamide is an acylanilid that has anti-androgen activity. Itis known to selectively decrease the testosterone level withoutinfluencing the regulation mechanisms of the hypothalamus.

[0005] The international patent No. WO 93/19770 describes both R-(−)enantiomer and S-(+) enantiomer for bicalutamide, of which the R-(−)isomer is reported to be more active and possesses lesser side-effects(e.g., headache, gynecomistia and giddiness) when used in therapytreatment.

[0006] U.S. Pat. No. 4,636,505 describes processes for preparingacylanilides.

[0007] The international Pat. No. WO 01/00608 describes a process forracemic and optically pureN-[4-cyano-3-trifluoromethylphenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamide.The process involves multiple steps including at least reacting withthionyl choride; hydrolyzing under aqueous basic conditions;sulfonylating with sulfonyl halogenide; and oxidizing with inorganicperoxy salt, or m-chloroperbenzoic acid (MCPBA) or aqueous hydrogenperoxide. However, the synthetic pathways involve the use of substrates(such as sodium hydride) that are dangerously explosive in nature.

[0008] There is a constant need to improve the synthesis process forbicalutamide which are economical and environmental safe and feasible.

[0009] We have now found a simpler method of preparing bicalutamide andits intermediates without using dangerous oxidizing compounds such asm-chloroperbenzoic acid.

OBJECTS AND SUMMARY OF THE INVENTION

[0010] The present invention provides new synthetic pathways forpreparing rac-bicalutamide and its intermediates.

[0011] According to one object, the present invention is directed to arac-bicalutamide intermediate having a chemical formula of [X], whichrepresents a stable organo lithium salt of 4-fluorophenyl methylsulfone.

[0012] According to another object, the present invention is directed toa process of preparing [X], comprising the step of reacting4-fluorophenyl methyl sulfone with butyl lithium to form the organolithium salt of 4-fluorophenyl methyl sulfone.

[0013] According to another object, the present invention provides anovel process for preparing rac-ethyl 1-[2-{4-fluorophenylsulfone}]-2-hydroxy propionic acid, comprising the step of reacting theorgano lithium salt of 4-fluorophenyl methyl sulfone with ethylpyruvate.

[0014] According to another object, the present invention is directed toa rac-bicalutamide intermediate having a chemical formula of [Y], whichrepresents a stable lithium salt of 5-amino-2-cyano-benzotrifluoride.

[0015] According to another object, the present invention provides aprecess for preparing [Y], comprising the step of reacting5-amino-2-cyano-benzotrifluoride with butyl lithium to form the lithiumsalt of 5-amino-cyano-benzotrifluoride.

[0016] According to another object, the present invention provides aprocess for preparing rac-bicalutamide, comprising the step of reacting[Y] with rac-ethyl 1-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionicacid.

[0017] According to another object, the present invention provides aprocess for preparing rac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxypropionic acid, comprising the steps of:

[0018] 1) mixing 4-fluorophenyl methyl sulfone with butyl lithium toobtain an intermediate having a chemical structure [X];

[0019] 2) adding ethyl pyruvate; and

[0020] 3) recovering rac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxypropionic acid.

[0021] Preferably, 1,4 diazabicyclo[2.2.2]octane in tetrahydrofuran isused as a stablizied agent in step 1.

[0022] According to another object, the present invention provides aprocess for preparign rac-bicalutamide comprising the steps of:

[0023] 1) mixing 5-amino-2-cyano-benzotrifluoride and butyl lithium toobtain a lithium salt of 5-amino-2-cyano-benzotrifloride;

[0024] 2) adding rac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxypropionic acid; and

[0025] 3) recovering rac-bicalutamide.

[0026] Preferably, the step 1) is occurred in the presence of 1,4diazabicyclo[2.2.2]octane in tetrahydrofuran.

[0027] According to one object, the present invention provides a novelprocess of preparing micronized forms of rac-bicalutamide.

[0028] According to another object, the present invention provides asynthesis process of preparing rac-bicalutamide with a particle size inwhich the mean particle size enhances the rate of dissolution and thereproducibility of dissolution. The present invention providesrac-bicalutamide in which the mean particle size imparts an improved andstable dissolution profile.

[0029] According to another object, the present invention providesrac-bicalutamide formulations containing rac-bicalutamide havingrelatively small particles, and corresponding large surface area.

[0030] According to another object, the present invention providesrac-bicalutamide with a particle size which enhances the rate ofdissolution and the reproducibility of the rate of dissolution.

[0031] According to another object, the present invention providesrac-bicalutamide in which the mean particle size imparts an improved andstable dissolution profile.

[0032] According to another object, the present invention providesrac-bicalutamide and formulations containing rac-bicalutamide having amean particle diameter of less than 200 μm.

[0033] According to another object, the present invention provides aprocess for preparing micronized rac-bicalutamide.

[0034] According to another object, the present invention providespharmaceutical compositions comprising micronized rac-bicalutamide.

BRIEF DESCRIPTION OF THE DRAWINGS

[0035]FIG. 1 depicts the reaction pathway of rac-bicalutamide synthesisstarting from ethyl pyruvate.

[0036]FIG. 2 depicts the reaction pathway of rac-bicalutamide synthesisstarting from methyl methacrylate.

DETAILED DESCRIPTION OF THE INVENTION

[0037] Definitions:

[0038] As used herein, rac-bicalutamide refers to both the R-(−)enantiomer and S-(+) enantiomer of bicalutamide. Rac-bicalutamide is theracemic and optically pure R-(−) and S-(+) isomers ofN-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamide.It is to be understood that this invention encompasses the racemic formof bicalutamide and any optically-active form which possessesanti-androgenic activity. It is a matter of common general knowledge howa racemic compound may be resolved into its optically-active forms andhow any anti-androgenic activity present in any of these forms may bedetermined. One skilled in the art will appreciate that the separationof optical isomers can be achieved by conventional resolution; such asfractional crystallization or flash-chromatography.

[0039] As used herein, the term “micronized” refers to particles havinga mean particle diameter of less than about 200 μm.

[0040] As used herein, the term “μm” refers to “micrometer” which is1×10⁻⁶ meter.

[0041] The following abbreviations are used herein: DCM isdichloromethane. THF is tetrahydrofuran. DABCO is 1,4 dizazbicyl [2.2.2]octane. ACB is 5-amino-2-cyano-benzotrofluoride. BCL israc-bicalutamide. 4-FPMS is 4-fluorophenyl methyl sulfone.

[0042] The present invention provides a novel process for preparingrac-bicalutamide from ethyl pyruvate and 4-fluoropheynl methyl sulfonevia the formation of an intermediate with chemical formula of [X].

[0043] The present invention further provides a novel process forpreparing rac-bicalutamide from 4-fluorophenyl methyl sulfone. Butyllithium reacts with 4-fluorophenyl methyl sulfone with a base to form anorgano lithium the intermediate (i.e., with chemical formula of [X]),optionally in the presence of anion stabilizer such as DABCO. The baserefers to strong bases such as lithium diisopropyl amid (LDA) or itsderivatives. This reaction is preferably carried out in an inert organicsolvent, for example tetrahydrofuran or diethyl ether. Most preferablesolvent is tetrahydrofuran. The reaction is preferably carried out at alow temperature, for example −40° C. to 10° C. Most preferabletemperature is between −2° C. and 2° C.

[0044]FIG. 1 illustrates the schematic process for preparingrac-bicalutamide from ethyl pyruvate and 4-fluorophenyl methyl sulfone.The intermediate with general chemical formula of [X] reacts with ethylpyruvate to form ethyl-[2-4-{4-fluorophenyl sulfone}]-2-hydroxypropionate. This reaction is preferably carried out in an inert organicsolvent, for example tetrahydrofuran or diethyl ether. Most preferablesolvent is tetrahydrofuran. The reaction is preferably carried out at alow temperature, for example −60° C. to −100° C. Most preferabletemperature is −60° C.

[0045] The present invention provides a process of preparingrac-bicalutamide from 5-amino-2-cyano-benzotrifluoride. Butyl lithiumreacts with 5-amino-2-cyano-benzotriflouride with a base to form anorgano lithium the intermediate (i.e., with chemical formula of [Y]),optionally in the presence of anion stabilizer such as DABCO. The baserefers to strong bases such as lithium diisopropyl amid (LDA) or itsderivatives. This reaction is preferably carried out in an inert organicsolvent, for example tetrahydrofuran or diethyl ether. Most preferablesolvent is tetrahydrofuran. The reaction is preferably carried out at alow temperature, for example −40° C. to 110° C. Most preferabletemperature is between −2° C. and 2° C.

[0046] The present invention provides a process of preparingrac-bicalutamide from 5-amino-2-cyano-benzotrifluoride via intermediatewith chemical formula of [Y]. Intermediate with chemcial formula [Y]thus formed reacts with rac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxypropionate to form rac-bicalutamide. This reaction is preferably carriedout in an inert organic solvent, for example tetrahydrofuran or diethylether. Most preferable solvent is tetrahydrofuran. The reaction ispreferably carried out at a low temperature, for example −60° C. to−100° C. Most preferable temperature is −60° C.

[0047] The detailed procedures of preparing rac-ethyl-[2-{4-fluorophenylsulfone}]-2-hydroxy propionic acid from ethyl pyruvate and4-fluorophenyl methyl sulfone as well as rac-bicalutamide fromrac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionic acid and5-amino-2-cyano-benzotrifluoride are illustrated in FIG. 1.

[0048] The process according to our invention is described in detail bythe following, but not limiting, examples.

EXAMPLE 1 Preparation of rac-Ethyl-[2-{4-FluorophenylSulfone}]-2-Hydroxy Propionate

[0049] 4-Fluorophenyl methyl sulfone (4-FPMS) (5 grams, 27.8 mmol) and1,4 diazabicyclo[2.2.2]octane (DABCO) (3.2 grams, 28.5 mmol) weredissolved in tetrahydrofuran (THF) and cooled in dry-ice acetone bath toabout −2° C.

[0050] A 2.5 M solution of butyl lithium in hexanes (14.5 mL, 36.2 mmol)was added to the cold THF solution dropwise via a syringe while keepingthe temperature between about −2° C. to about 2° C. After addition wascompleted the stirring was continued for about 1 hour while maintainingthe temperature at about −2° C. Then, the temperature was lowered toabout −65° C. and a solution of ethyl pyruvate (3.67 grams, 31.6 mmol)in THF (30 mL) was added dropwise.

[0051] After addition was completed, the stirring was continued for anhour at temperatures between about −65° C. and about −30° C. and thenfollowed by an addition of 2N HCl (30 mL) dropwise to the reactionmixture at about −30° C. The reaction was allowed to warm-up to roomtemperature and the mixture was evaporated in vacuo on a rotaryevaporator to remove THF and ethanol.

[0052] The residual material was extracted with diethyl ether (3×100mL). The combined ether extracts were dried over Na₂SO₄, filtered andthe filtrate was completely evaporated to give a crude oil.

[0053] The product was purified by column chromatography on silica gelvia eluting with dichloromethane (DCM) to giverac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate as colorlessoil.

[0054] The purified product was characterized by a ¹H NMR (500 MHz,CDCl₃): 7.92 (m, 2H), 7.22 (m, 2H), 4.29 (m, 2H, OCH₂), 3.77 (d, J=15Hz, 1H, CH_(2α)), 3.68 (bs, 1H, OH), 3.55 (d, J=15 Hz, 1H, CH₂), 1.45(s, 3H, Me), 1.35 (t, J=7 Hz, 3H, OCH₂CH₃).

[0055] The purified product was further characterized by a ¹³C NMR(125.7 MHz, CDCl₃): 174.7 ppm (CO_(ester)), 166.4 (C-4′, J_(C-F)=258Hz), 137.5 ((c-1′), 131.7 (C-2′,6′, J_(C-F)=9 Hz), 117.0 (C-3′,5′,J_(C-F)=21.6 Hz), 72.9 (C_(quat)), 64.6 (CH₂), 63.6 (OCH₂), 27.9 (CH₃),14.7 (OCH₂CH₃).

[0056] The purified product was further characterized by HPLC(acetonitrile:water 1:1 with 0.01% TFA): 5.4 mins.

EXAMPLE 2 Preparation ofrac-N-[4-Cyano-3-Trifluoromethyl-Phenyl]-3-[4-FluorophenylSulfonyl]-2-Hydroxy-2-Methyl-Propionamide

[0057] 5-Amino-2-cyano-benzotrifluoride (ACB) (0.27 grams, 1.45 mmol)and 1,4 diazabicyclo[2.2.2]octane (DABCO) (0.32 grams, 2.85 mmol) weredissolved in tetrahydrofuran (THF) (30 mL) and cooled in dry-ice acetonebath to about −2° C.

[0058] A 2.5M solution of butyl lithium in hexanes (2 mL, 5 mmol) wasadded to the cold THF solution dropwise via a syringe while keeping thetemperature between about −2 to about 2° C. After addition wascompleted, the stirring was continued for 1 hour while maintaining thetemperature at about −2° C. The temperature was then lowered to about−65° C. and a solution of rac-Ethyl-[2-{4-fluorophenylsulfone}]-2-hydroxy propionate (0.34 grams, 1.17 mmol) in THF (20 mL)was added dropwise.

[0059] After addition was completed, the stirring was continued for anhour at temperatures between about −65° C. and about −30° C. after which2N HCl (30 mL) was added dropwise to the reaction mixture at about −30°C. The reaction was allowed to warm-up to room temperature and themixture was evaporated in vacuo on a rotary evaporator to remove THF andethanol.

[0060] The residual material was extracted with diethyl ether (3×100mL). The combined ether extracts were dried over Na₂SO₄, filtered andthe filtrate was completely evaporated to give a crude oil.

[0061] The product was purified by column chromatography on silica geleluting with ethyl acetate—petroleum ether to giverac-N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenylsulfonyl]-2-hydroxy-2-methyl-propionamide in about 40% yield, as a paleyellow solid.

[0062] The present invention further provides a novel process forpreparing rac-bicalutamide from methyl methacrylate. FIG. 2 illustratesthe schematic process for preparing rac-bicalutamide from methylmethacrylate.

[0063] According to FIG. 2, the starting material was methylmethacrylate, which can usually be converted into the epoxide only underharsh conditions (i.e. with peracetic acid in ethyl acetate at 75° C.[J. A. Chem., 81, 680 (1959)], or with 90% hydrogenperoxide-trifluoroacetic anhydride at 40° C. [J. Am. Chem., 77, 89(1955)], or with MCPBA in dichloromethane at 0° C. in low yield [J. Med.Chem., 29, 2184 (1986)]. The epoxidation under these conditions can beexplosive. The present invention describes this oxidation using Oxone®.

[0064] The methyl 2-methyl-oxirane-carboxylate of formula (1), which wasobtained by epoxidation, was reacted with 4-fluorothiophenol [formula(2)] in the presence of sodium hydride under the conditions listed inScheme-2. The obtained methyl2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionate of formula (3) washydrolyzed with potassium hydroxide in aqueous ethanol over a period of22 hours to yield the2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionic acid of formula (4),which was converted into the acid chloride of formula (5) with thionylchloride in dimethyl acetamide at −15° C.

[0065] The obtained acid chloride was reacted with4-amino-2-trifluoromethyl-benzonitrile in dimethylacetamide at −15° C.to yield the thioether derivative of formula (6). The oxidation of thethioether derivative was carried out by known method withm-chloroperbenzoic acid in dichloromethane to yield the final product,bicalutamide, of formula (7).

[0066] The process according to our invention is described in detail bythe following, but not limiting, examples.

EXAMPLE 3 Preparation of Methyl 1,2-Epoxy-2-Methyl-Propionate

[0067] In a 3L four-neck round bottom flask, Oxone® (50% KHSO₅, 227grams, 0.75 mol) was dissolved in water (1L) and 10 M KOH was added toadjust the pH to ˜6 (˜53 mL). Then, methyl methacrylate (13 mL, 0.122mol) in methanol was added (50 mL) followed by 360 mL of water.

[0068] The solution was stirred at room temperature and the pH wascontinuously adjusted to pH=6 with 1M KOH (˜270 mL). After 6 hr thereaction was stirred over night. Then, 2N HCl was added (100 mL, pH=3)and the entire aqueous solution was extracted with DCM (3×150 mL) foreach 400 mL reaction solution. The combined DCM extracts were washedwith saturated sodium sulfite solution followed by saturated sodiumbicarbonate solution.

[0069] After drying and filtartion, DCM was removed by evaporation andthe unreacted methyl methacrylate was distilled out. The residuecontained the product as an oily material.

[0070] GC: (>97%, 1.45 min); yield: 66%; ¹H NMR (500 MHz, CDCL₃; □ppm3.72 (s,3H, Me), 3.07 (dd, J=6 Hz, J=16 Hz, 1H, H_(□)), 2.73 (d, J=6 Hz,1H, H_(□)), 1.55 (s, Me); ¹³C-NMR (125.7 MHz, CDCL₃; □ ppm): 172(CO_(ester)), 54.3 (CH₂), 53.6 (C_(quat)), 53.2 (Me_(ester)), 18 (Me).

EXAMPLE 4 Preparation of 2-Hydroxy-2-Methyl-3-(4-Fluorophenylthio)Propionic Acid

[0071] To a solution of 4-fluorothiophenol (1 mL) in MeOH (32 mL) wasadded dropwise 2N NaOHaq. (16 mL) under N₂, while the temperature waskept at 25° C. during the addition period. When addition was completed,the reaction mixture was stirred at room temperature for a further 90min.

[0072] A solution of methyl-1,2-epoxy-2-methyl propionate (1.2 gram) inMeOH (20 mL) was then added dropwise at room temperature. When additionwas completed, the reaction mixture was stirred over night at ambienttemperature. To the reaction mixture 2N HCl (20 mL) was added followedby ethyl acetate (60 mL). The organic phase was separated. The aqueousphase (pH˜2) was extracted with 60 mL of chloroform and then discarded.The ethyl acetate and chloroform extracts were combined.

[0073] After drying (MgSO₄) and filtration, the two organic solventswere evaoprated to leave an oily product which solidified upon standingat room temperature.

[0074] Purity: 75% (according to GC); Yield: 66%. GCMS: 230 m/z (13%);M.p.: 69.1-72.7° C; ¹H NMR (500 MHz, CDCL₃; □ppm 7.43 (m, 2H, H-2′,6′),6.96 (m, 2H, H-3′,5′), 3.39 (d, J=14 Hz, 1H, H_(□)), 3.17 (d, J=14 Hz,1H, H_(□)), 1.53 (s, Me); ¹³C-NMR (125.7 MHz, CDCL₃; □ ppm): 180.4(CO_(acid)), 162.6 (d, J_(C-F)=248 Hz, C-4′), 134.3 (d, J_(C-F)=7.5 Hz,C-2′,6′), 130.8 (d, J_(C-F)=3.2 Hz, C-1′), 116.5 (d, J_(C-F)=21.6 Hz,C-3′,5′), 75.2 (C_(quat)), 53.3 (Me_(ester)), 46.4 (CH₂), 26.0 (Me).

Micronized Rac-Bicalutamide

[0075] The Particle Size Distribution (PSD) of rac-bicalutamide may beused to determine the available surface area for the drug dissolution.Often, it is observed that the available surface area for drugdissolution correlates to both (a) the rate of dissolution andsolubility where a great surface area enhances the solubility of a drug;and (b) enhances the rate of dissolution of a drug. The rate ofdissolution of a drug effects the drug's bioavailability. Thus, the PSDof rac-bicalutamide, and in particular, the meagrn particle diameter,are important parameters to characterize and predict the bioavailibilityof rac-bicalutamide.

[0076] The present invention provides rac-bicalutamide formulationscontaining rac-bicalutamide having relative small particles andcorresponding relatively large surface area.

[0077] The present invention provides rac-bicalutamide formulationscontinaing rac-bicalutamide having a mean particle diameter of less than200 μm, preferably the mean particle diameter is less than 100 μm, morepreferably the mean particle diameter is less than 20 μm, and mostpreferably the mean particle size is about 10 μm.

[0078] The present invention provides rac-bicalutamide having a meanparticle diameter of between about 200 μm and about 10 μm. In oneembodiment of the invention, rac-bicalutamide has a mean diameter ofabout 4.2 μm, more preferabley a mean diameter of 4.0 μm.

[0079] The present invention also provides process for preparingmicronized rac-bicalutamide. By the methods of the present invention,rac-bicalutamide, which is prepared by methods known in the art, isseparated by sieves to produce rac-bicalutamide wherein 50% has a meanparticle diameter of below about 250 μm and about 80% has a meanparticle diameter of below about 500 μm. The sieved rac-bicalutamide isthen micronized by methods known in the art, e.g., in a micronizer, toyield rac-bicalutamide wherein 100% of rac-bicalutamide has a meanparticle size of less than about 45 μm, preferably 99% of therac-bicalutamide has a mean particle size of less than about 45 μm, morepreferably, 93% of the rac-bicalutamide has a mean particle size of lessthan about 7.5 μm, more preferably the rac-bicalutamide isolated has amean particle diameter of less than about 10 μm.

[0080] Micronized particles of rac-bicalutamide can be obtained by theuse of conventional micronizing techniques after sieving to providerac-bicalutamide wherein about 50% has a particle size of less thanabout 250 μm and about 80% has a particle size of less than 500 μm. Bythe methods of the present invention, the rac-bicalutamide where about50% has a particle size less than 500 μm and about 80% has a particlesize below about 500 μm, is micronized to the desired particle sizerange by methods known in the art, for example, using a ball mill,ultraonic means, fluid energy attrition mills, or using a jet mill, orother suitable means as disclosed in Pharmaceutical Dosage Forms:Tablets, Vol. 2, 2^(nd) Ed., Lieberman et al. Ed., Marcel Dekker, Inc.New York (1990) p. 107-200, the content of which is incorporated byreference herein.

[0081] The present invention provides micronized rac-bicalutamide aspharmaceutical compositions that are particularly useful for itsanti-androgen activity. Such compositions comprise micronizedrac-bicalutamide with pharmaceutically acceptable carriers and/orexcipients known to one of skilled in the art.

[0082] Preferably, these compositions are prepared as medicaments to beadministered orally or intravenously. Suitable forms for oraladministration niclude tablets, compressed or coated pills, dragees,sachets, hard or gelatin capsules, sub-lingual tablets, syrups andsuspensions. While one of ordinary skill in the art will understand thatdosages will vary according to the indication, age and severity of thedisease of the patent etc., generally micronized rac-bicalutamide of thepresent invention will be administered at a daily dosage of about 2 mgto about 200 mg per day, and preferably about 5 mg to about 100 mg perday.

What is claimed is:
 1. A rac-bicalutamide intermediate having thechemical strcuture of [X], wherein [X] is a stable organo lithium saltof 4-fluorophenyl methyl sulfone.
 2. A process of preparing arac-bicalutamide intermediate having the chemical structure of [X],comprising the steps of: a) dissovling 4-fluorophenyl methyl sulfone inan organic solvent; and b) adding butyl lithium to the solution, whereinbutyl lithium reacts with 4-fluorophenyl methyl sulfone to form [X]. 3.The process according to claim 2, wherein the organic solvent isselected from the group consisting of tetrahydrofuran and diethyl ether.4. The process according to claim 2, wherein the reaction between butyllithium with 4-fluorophenyl methyl sulfone occurs in the presence of ananion stabilizer.
 5. The process according to claim 4, wherein the anionstabilizer is 1,4 diazabicylo[2.2.2]octane.
 6. The process according toclaim 2, wherein the reaction between butyl lithium with 4-fluorophenylmethyl sulfone occurs in a temperature range between about −40° C. toabout +10° C.
 7. The process according to claim 2, wherein the reactionbetween butyl lithium with 4-fluorophenyl methyl sulfone occurs in atemperature range between about −2° C. and about +2° C.
 8. A process ofpreparing ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate,comprises the steps of: a) preparing a mixture of 4-fluorophenyl methylsulfone and butyl lithium in an organic solvent; b) adding ethylpyruvate; and c) recovering ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxypropionate.
 9. The process according to claim 8, wherein the organicsolvent is tetrahydrofuran.
 10. The process according to claim 8,wherein the ethyl pyruvate is added to the mixture at a temperature ofabout −65° C.
 11. The process according to claim 8, wherein therecovering step comprises evaporating the mixture containing ethylpyruvate.
 12. The process according to claim 8, wherein the recoveringstep further comprises separating the ethyl-[2-{4-fluorophenylsulfone}]-2-hydroxy propionate.
 13. A rac-bicalutamide intermediatehaving the chemical strcuture of [Y], wherein [Y] is a stable organolithium salt of 5-amino-2-cyano-benzotrifluoride.
 14. A process ofpreparing a rac-bicalutamide intermediate having the chemical structureof [Y], comprising the steps of: a) dissovling5-amino-2-cyano-benzotriflouride in an organic solvent; and b) addingbutyl lithium to the solution, wherein butyl lithium reacts with5-amino-2-cyano-benzotrifloride to form [Y].
 15. The process accordingto claim 14, wherein the organic solvent is selected from the groupconsisting of tetrahydrofuran and diethyl ether.
 16. The processaccording to claim 14, wherein the reaction between butyl lithium with5-amino-2-cyano-benzotrifloride occurs in the presence of an anionstabilizer.
 17. The process according to claim 16, wherein the anionstabilizer is 1,4 diazabicylo[2.2.2]octane.
 18. The process according toclaim 14, wherein the reaction between butyl lithium with5-amino-2-cyano-benzotrifloride occurs in a temperature range betweenabout −40° C. to about +10° C.
 19. The process according to claim 14,wherein the reaction between butyl lithium with5-amino-2-cyano-benzotrifloride occurs in a temperature range betweenabout −2° C. and about +2° C.
 20. A process of preparingrac-bicalutamide, comprising the steps of: a) preparing a mixture of5-amino-2-cyano-benzotrifluoride and butyl lithium in an organicsolvent; b) adding ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxypropionic acid to the mixture; and c) recovering rac-bicalutamide. 21.The process according to claim 20, wherein the organic solvent isselected from the group consisting of tetrahydrofuran and diethyl ether.22. The process according to claim 20, wherein theethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionic acid is added tothe mixture at a temperature of about −65° C.
 23. The process accordingto claim 20, wherein recovering step comprises evaporating the mixturecontaining ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionic acid.24. The process according to claim 20, wherein the recovering stepfurther comprises separating the ethyl-[2-{4-fluorophenylsulfone}]-2-hydroxy propionic acid.
 25. The process according to claim20, wherein the rac-bicalutamide is an R-isomer.
 26. The processaccording to claim 20, wherein the rac-bicalutamide is an S-isomer. 27.A process of preparing methyl 1,2-epoxy-2-methyl propionate, comprisingthe steps of: a) dissolving oxone in a basic solution; b) adding methylmethacrylate to the oxone solution; c) adding an acid to the oxonesolution to form methyl 1,2-epoxy-2-methyl propionate; and d) recoveringmethyl 1,2-epoxy-2-methyl propionate.
 28. The process according to claim27, wherein the basic solution is selected from the group consisting ofpotassium hydroxide and sodium hydroxide.
 29. The process according toclaim 28, wherein the potassium hydroxide has a concentration of 10 M.30. The process according to claim 27, wherein the oxone is 50% KHSO₅.31. The process according to claim 27, wherein the methyl methacrylateis added in methanol.
 32. The process according to claim 27, wherein theoxone solution containing methyl methacrylate is maintained at about pH6.
 33. The process according to claim 27, wherein the acid is selectedfrom the group consisting of hydrochloric acid, nitric acid andphosphoric acid.
 34. The process according to claim 33, wherein thehydrochloric acid has a concentration of about 0.05 N to about 5 N. 35.A process of preparing 2-hydroxy-2-methyl-3-(4-fluorophenylthio)propionic acid, comprising the steps of: a) preparing a solution of4-fluorothiophenol in methanol; b) adding methyl-1,2-epoxy-2-methylpropionate to form a mixture; c) adding ethyl acetate to the mixture;and d) recovering 2-hydroxy-2-methyl-3-(4-fluorophenylthio) propionicacid.
 36. The process according to claim 35, wherein the preparation of4-fluorothiophenol solution is performed by adding a basic solutionunder N₂ flow.
 37. The process according to claim 36, wherien the basicsolution is selected from the group consisting of sodium hydroxide andpotassium hydroxide.
 38. The process according to claim 37, wherein thesodium hydroxide has a concentration of 2 N.
 39. The process accordingto claim 35, wherein the mixture is formed by stirring.
 40. The processaccording to claim 39, wherein the stirring is performed at roomtemperature for 90 minutes.
 41. The process according to claim 35,wherein the recovering step is extraction.
 42. The process according toclaim 41, wherein the extraction is achieved by chloroform.
 43. Theprocess according to claim 35, wherein the recovering step furtherinvolves solidifying 2-hydrox-2-methyl-3-(4-fluorophenylthio) propionicacid.
 44. A micronized rac-bicalutamide, wherein the micronizedrac-bicalutamide has a mean particle diameter of less than about 200 μm.45. A micronized rac-bicalutamide, wherien the micronizedrac-bicalutamide has a mean particle diameter of less than about 100 μm.46. A micronized rac-bicalutamide, wherein the micronizedrac-bicalutamide has a mean particle diameter of less than 10 μm.
 47. Amicronized rac-bicalutamide, wherein the micronized rac-bicalutamide hasa mean particle diameter between about 200 μm to about 10 μm.
 48. Apharmaceutical composition of rac-bicalutamide comprising a micronizedrac-bicalutamide and a pharmaceutically acceptable salt.
 49. Thepharmaceutical composition of rac-bicalutamide wherein the micronizedrac-bicalutamide has a mean particle diameter between about 200 μm toabout 10 μm.